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Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8⁺ T Cell Function and Memory Development¹

Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom

After priming, naive T cells undergo a program of expansion, contraction, and memory formation. Numerous studies have indicated that only a brief period of antigenic stimulation is required to fully commit CD8⁺ T cells to this program. Nonetheless, the persistence of Ag may modulate the eventual fate of CD8⁺ T cells. Using DNA delivery, we showed previously that direct presentation primes high levels of effector CD8⁺ T cells as compared with cross-presentation. One explanation now revealed is that prolonged cross-presentation limits effector cell expansion and function. To analyze this, we used a drug-responsive system to regulate Ag expression after DNA injection. Reducing expression to a single burst expanded greater numbers of peptide-specific effector CD8⁺ T cells than sustained Ag. Consequences for memory development were assessed after boosting and showed that, although persistent Ag maintained higher numbers of tetramer-positive CD8⁺ T cells, these expanded less (4-fold) than those induced by transient Ag expression (35-fold). Transient expression at priming therefore led to a net higher secondary response. In terms of vaccine design, we propose that the most effective DNA-based CD8⁺ T cell vaccines will be those that deliver a short burst of Ag.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Leukaemia Research Fund Grant 0308.

² Address correspondence and reprint requests to Dr. Stephen M. Thirdborough, Somers Cancer Research Building, Mail Point 824, Southampton General Hospital, Southampton, SO16 6YD, U.K. E-mail address: S.M.Thirdborough{at}soton.ac.uk

³ Abbreviations used in this paper: MFP, mifepristone; MFI, mean fluorescence intensity.

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The JI 2007 179: 7991-7992. [Full Text]  

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